Compositions and methods for treatment of erectile dysfunction

ABSTRACT

The subject invention pertains to methods and compositions for the treatment of erectile dysfunction (ED) (e.g., impotence) in a subject in need thereof utilizing one or more cannabinoid and one or more anti-ED drug.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims benefit from U.S. Provisional Patent ApplicationNo. 62/433,502, entitled “Compositions and Methods for Treatment ofErectile Dysfunction,” filed on Dec. 13, 2016, which is herebyincorporated in its entirety by reference.

BACKGROUND

Erectile dysfunction (ED) or impotence is a sexual dysfunctioncharacterized by the inability to develop or maintain an erection of thepenis during sexual activity. A penile erection is the hydraulic effectof blood entering and being retained in sponge-like bodies within thepenis. The process is most often initiated as a result of sexualarousal, when signals are transmitted from the brain to nerves in thepenis. The most important organic causes are cardiovascular disease anddiabetes, neurological problems (for example, trauma from prostatectomysurgery), hormonal insufficiencies (hypogonadism) and drug side effects.

The study of ED within medicine is covered by andrology, a sub-fieldwithin urology. Research indicates that ED is common, and it issuggested that approximately 40% of males suffer from ED or impotence,at least occasionally. Current treatments for ED include drugs such as,for example, vardenafil, avanafil, sildenafil, tadalafil, andalprostadil. Furthermore, there are studies suggesting that naturalherbals, such as damiana, horny goat weed, and yohimbine, are alsoeffective in treating ED.

BRIEF SUMMARY

In one aspect, the subject disclosure provides methods for treatmentand/or prevention of erectile dysfunction (ED) in a subject in needthereof. One advantage of the invention is that it reduces or eliminatesside effects experienced by users of AEDs., such as for example,headache, dizziness, etc.

In some embodiments, cannabis, or extract thereof, is administered in anamount from about 5 mg to about 50 mg.

In another aspect, the subject disclosure provides a composition fortreatment of ED. The composition may comprise a therapeuticallyeffective amount of an anti-erectile dysfunction drug (AED), orpharmaceutically acceptable salt thereof; and cannabis, or an extractthereof.

In some embodiments of the aspects described, the AED may comprisevardenafil, avanafil, sildenafil, tadalafil, alprostadil, damiana, hornygoat weed, and/or yohimbine.

In some embodiments, the cannabis extract comprises at least onecannabinoid. In some embodiments, the cannabis extract comprisescannabidiol (CBD). In some embodiments, the cannabis extract comprisescannabinoid tetrahydrocannabinol (THC). In some embodiments, thecannabis extract comprises cannabidiolic acid (CBDA). In someembodiments, the cannabis extract comprises cannabidivarin (CBDV). Insome embodiments, the cannabis extract comprises cannabidivarinic acid(CBDVA). In some embodiments, the cannabis extract comprisestetrahydrocannabinol (THC).

In another aspect, the subject disclosure provides a pharmaceuticalcomposition comprising a therapeutically effective amount of ananti-erectile dysfunction drug (AED), or pharmaceutically acceptablesalt thereof; and cannabis, or an extract thereof; and apharmaceutically acceptable carrier. In some embodiments, the cannabis,or extract thereof, concentration is from about 5 mg to about 50 mg.

DETAILED DISCLOSURE

The present disclosure pertains to compositions and methods for thetreatment and/or prevention of erectile dysfunction (ED).

Several aspects of the disclosure are described below, with reference toexamples for illustrative purposes only. It should be understood thatnumerous specific details, relationships, and methods are set forth toprovide a full understanding of the disclosure. One having ordinaryskill in the relevant art, however, will readily recognize that theaspects described can be practiced without one or more of the specificdetails or practiced with other methods, protocols, reagents, andanimals. The aspects described are not limited by the illustratedordering of acts or events, as some acts may occur in different ordersand/or concurrently with other acts or events. Furthermore, not allillustrated acts, steps or events are required to implement amethodology in accordance with the aspects described. Many of thetechniques and procedures described, or referenced herein, are wellunderstood and commonly employed using conventional methodology by thoseskilled in the art.

Prior to setting forth aspects of the disclosure in detail, it may behelpful to the understanding thereof to define several terms, and theseare accordingly set forth in the next section, below. Unless otherwisedefined, all terms of art, notations and other scientific terms orterminology used herein are intended to have the meanings commonlyunderstood by those of skill in the art to which this disclosurepertains. In some cases, terms with commonly understood meanings aredefined herein for clarity and/or for ready reference, and the inclusionof such definitions herein should not necessarily be construed torepresent a substantial difference over what is generally understood inthe art. It will be further understood that terms, such as those definedin commonly used dictionaries, should be interpreted as having a meaningthat is consistent with their meaning in the context of the relevant artand/or as otherwise defined herein.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting. As used herein, theindefinite articles “a”, “an” and “the” should be understood to includeplural reference unless the context clearly indicates otherwise.

The phrase “and/or,” as used herein, should be understood to mean“either or both” of the elements so conjoined, i.e., elements that areconjunctively present in some cases and disjunctively present in othercases.

As used herein, “or” should be understood to have the same meaning asdefined above for “and/or”. For example, when separating a listing ofitems, “and/or” or “or” shall be interpreted as being inclusive, i.e.,the inclusion of at least one, but also including more than one, of anumber of items, and, optionally, additional unlisted items. Only termsclearly indicated to the contrary, such as “only one of” or “exactly oneof,” or, when used in the claims, “consisting of,” will refer to theinclusion of exactly one element of a number or list of elements. Ingeneral, the term “or” as used herein shall only be interpreted asindicating exclusive alternatives (i.e., “one or the other but notboth”) when preceded by terms of exclusivity, such as “either,” “oneof,” “only one of,” or “exactly one of.”

As used herein, the terms “including”, “includes”, “having”, “has”,“with”, or variants thereof, are intended to be inclusive similar to theterm “comprising.”

As used herein, the term “subject” refers to an animal. Typically, theterms “subject” and “patient” may be used interchangeably herein inreference to a subject. As such, a “subject” includes an animal that isbeing treated for erectile dysfunction, or the recipient of a mixture ofcomponents or compositions as described herein. The term “animal,”includes, but is not limited to, a mammal, such as a mouse, rat, dog,guinea pig, cow, horse, chicken, cat, rabbit, pig, monkey, chimpanzee,and human.

The term “effective amount” or “therapeutically effective amount” meansthat amount of active compound that elicits the biological or medicinalresponse in a tissue system, animal or human that is being sought by aresearcher, veterinarian, medical doctor or other clinician, whichincludes alleviation of one or more of the symptoms of the disease ordisorder being treated; reduction of the severity of one or more of thesymptoms of the disease or disorder being treated; or otherwise providesthe desired effect. The precise dosage will vary according to a varietyof factors such as subject-dependent variables (e.g., age, medicalhistory, etc.), the disorder or condition, and the treatment beingaffected. In particular aspects of the present disclosure directed toco-therapy or combination therapy, comprising administration of one ormore anti-ED agents and a cannabis extract or one or more cannabinoids(or synthetic variants thereof), therapeutically effective amount meansthat amount of the combination of agents taken together so that thecombined effect elicits the desired biological or medicinal response.For example, the therapeutically effective amount of co-therapycomprising administration of an anti-ED agent and a cannabinoid would bethe amount of the cannabinoid and the amount of the suitable anti-EDagent that, when taken together or sequentially, have a combined effectthat is therapeutically effective. Further, it will be recognized by oneskilled in the art that in the case of co-therapy with a therapeuticallyeffective amount, as in the example above, the amount of cannabinoid orthe amount of the suitable anti-ED agent individually may or may not betherapeutically effective.

The term “pharmaceutically acceptable,” as used herein, means approvedby a regulatory agency of the Federal or a state government or listed inthe U.S. Pharmacopeia or other generally recognized pharmacopeia for usein animals and/or in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of thedisclosure that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. Such saltsinclude: (1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound isreplaced.

Aspects of the present disclosure provide compositions comprising thefollowing active ingredients: cannabis, a cannabis extract, or one ormore cannabinoid (or synthetic variant thereof); and one or more anti-EDagents. The compositions described can also be in the form of apharmaceutical composition comprising one or more pharmaceuticallyacceptable carriers described herein. The compounds and compositions ofthe disclosure can be used to treat, alleviate, inhibit or prevent ED.In some embodiments, the cannabis, or extract thereof, concentration isfrom about 5 mg to about 50 mg. For example, THC in a concentration fromabout 5 mg to about 50 mg may be used or provided.

The term “carrier” refers to a diluent, adjuvant, excipient, and/orvehicle with which the compositions are administered. Suchpharmaceutical carriers can be sterile liquids, such as water and oils,including those of petroleum, animal, vegetable or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil and the like.Saline solutions and aqueous dextrose and glycerol solutions can also beemployed as liquid carriers, particularly for injectable solutions.Suitable pharmaceutical excipients include starch, glucose, sucrose,gelatin, lactose, malt, rice, flour, chalk, silica gel, sodium stearate,glycerol monostearate, talc, sodium chloride, glycerol, propylene,glycol, water, ethanol and the like. The pharmaceutical composition(s)may also contain wetting or emulsifying agents or suspending/dilutingagents, or pH buffering agents, or agents for modifying or maintainingthe rate of release of the formulations. The compositions can take theform of solutions, suspensions, emulsion, tablets, pills, capsules,powders, gels, creams, cigar/cigarette, sustained-release formulationsand the like. Formulations can include standard carriers such aspharmaceutical grades of mannitol, lactose, sodium saccharine, starch,magnesium stearate, cellulose, magnesium carbonate, etc. Suchcompositions will contain an effective amount of the activeingredient(s) together with a suitable amount of carrier so as toprovide the proper form to the subject based on the mode ofadministration to be used.

If for intravenous administration, the compositions are packaged insolutions of sterile isotonic aqueous buffer. Where necessary, thecomposition may also include a solubilizing agent. The components of thecomposition are supplied either separately or mixed together in unitdosage form, for example, as a dry lyophilized powder or concentratedsolution in a hermetically sealed container such as an ampoule orsachette indicating the amount of active agents. If the composition isto be administered by infusion, it can be dispensed with an infusionbottle containing sterile pharmaceutical grade water or saline. Wherethe composition is administered by injection, an ampoule of sterilewater or saline can be provided so that the ingredients may be mixedprior to injection.

Moreover, if a packaging material is utilized to package thecomposition, it may be biologically inert or lack bioactivity, such asplastic polymers, silicone, etc. and may be processed internally by thesubject without affecting the effectiveness of the components packagedand/or delivered therewith. Additionally, the compositions andcomponents may be packaged with additional agents.

In some embodiments, the compositions comprise cannabis, in whole or inpart, from the bud of a marijuana plant. In other embodiments, thecompositions comprise an extract of cannabis. The extract may compriseone or more cannabinoid selected from cannabidiol (CBD),tetrahydrocannabinol (THC), cannabidiolic acid (CBDA), cannabidivarin(CBDV), and cannabidivarinic acid (CBDVA). Alternatively, one or more ofthe cannabinoids may be utilized in the methods and compositionsprovided in an isolated or purified form. Further, synthetic variants ofthe cannabinoids may be utilized, either individually or in combinationwith other synthetic cannabinoid variants or in combination withnon-synthetic cannabinoids.

In some embodiments, the cannabinoid used is in the form of a highlypurified extract of cannabis such that the cannabinoid is present atgreater than 98% of the total extract (w/w). In some embodiments, thecannabinoid tetrahydrocannabinol (THC) has been substantially removed,to a level of not more than 0.15% (w/w). Alternatively, the cannabinoidmay be a synthetically produced cannabinoid.

In some embodiments, the compositions also comprise an anti-ED drug (orextract). The anti-ED drug may include one or more of vardenafil,avanafil, sildenafil, tadalafil, and alprostadil. The anti-EDdrug/extract may also include one or more extracts of damiana, hornygoat weed, and yohimbine. Damiana, horny goat weed, and yohimbine may beutilized in the compositions and methods described as either liquidextracts, dried powders, or lyophilized extracts. Alternatively,purified extracts comprising the active ingredients from one or more ofeach of damiana, horny goat weed (e.g., epimedium), and yohimbine may beutilized. Likewise, synthetic variants of the active ingredients fromone or more of damiana, horny goat weed, and yohimbine may be utilizedin the compositions and methods described. The synthetic variants canalso be utilized in combination with one or more purified extracts.

Aspects of the present disclosure also provide kits comprising one ormore cannabis extract or cannabinoid-anti-ED formulations, or individualformulations, as described herein. The kits may further be used in themethods described herein. The kits may also include at least one reagentand/or instructions for their use. Also, the kit may include one or morecontainers filled with reagent(s) and/or one or more components of thedisclosure. One or more container of the kits provided may also comprisea cannabinoid, preferably in a purified form. One or more container ofthe kits provided may alternatively comprise a cannabis extract. Also,one or more container of the kits provided may also comprise an anti-EDagent, preferably in a purified form. In some embodiments, the cannabisextract or cannabinoid and anti-ED agent may be provided in separatecontainers for mixing prior to use, or for individualingestion/administration. The kits may also comprise a controlcomposition, such as reagents that lack a cannabinoid (or syntheticvariant) and/or anti-ED agent for use as a control reagent inexperimentation. As it would be understood by those skilled in the art,detection or labeling methodologies can be used in the kits providedwhen utilized in an experimental or laboratory setting.

Aspects of the present disclosure are further directed to methods oftreatment/prevention which involve administering therapeuticallyeffective amounts of a cannabis extract or one or more cannabinoid (orsynthetic variant thereof) and an anti-ED agent, or pharmaceuticalcompositions of the present disclosure, to a subject, preferably amammal, and most preferably a human, for treating and/or preventingerectile dysfunction (e.g, impotence). In some embodiments, thecannabis, or extract thereof, concentration utilized in the methodsdescribed is from about 5 mg to about 50 mg. For example, THC in aconcentration from about 5 mg to about 50 mg may be used or provided.

“Preventing” or “prevention” refers to a reduction in risk of acquiringdisorder (i.e., causing at least one of the clinical symptoms of thedisease/disorder not to develop in a subject that may be predisposed tothe disorder but does not yet experience or display symptoms of thedisorder).

“Treating” or “treatment” of any disorder refers, in one embodiment, toameliorating the disorder (i.e., arresting or reducing the developmentof the disorder (i.e., impotence) or at least one of the clinicalsymptoms thereof). In another embodiment “treating” or “treatment”refers to ameliorating at least one physical parameter, which may not bediscernible by the subject. In yet another embodiment, “treating” or“treatment” refers to modulating the disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both. In yet anotherembodiment, “treating” or “treatment” refers to delaying the onset ofthe disorder.

Administration can be locally (confined to an area of body) and/orsystemically in the subject. It may be desirable to administer thecannabis extract or cannabinoid/anti-ED agent combination, orpharmaceutical compositions comprising same, locally to the area in needof treatment, such as the groin rejoin or penis. This method ofadministration may be achieved by, for example, and not by way oflimitation, local infusion, topical application, by injection, bycatheter, or by means of an implant (e.g., a porous membrane).Administration may also be orally, such as but not limited to, by way ofpills, capsules, liquid, vapors, or smoking.

It is also understood and contemplated that aspects of this disclosurecan provide more than two active ingredient components in the mixturesof compositions herein disclosed. Also, the disclosed methods cancomprise the simultaneous or separate administration of multiple activeingredients. Thus, embodiments may further include the administration ofa third, fourth, etc. active ingredient, wherein the third, fourth, etc.active ingredient is administered separately, but at the same time asthe other active ingredients, or hours or days after the firstadministration of active ingredients.

In some embodiments, the cannabis extract or cannabinoid(s) and anti-EDagent(s), or pharmaceutical composition containing them, can bedelivered in a controlled release system. Such methods may include theuse of a pump for administration (e.g., use of an intravenous drip). Inanother embodiment, a controlled release system can be placed in theproximity of the therapeutic target (e.g., groin or penis), requiringonly a fraction of the dose required if dosed systemically.

The compounds and compositions of the invention may also be utilized inpharmaceutically acceptable compositions in the methods provided herein.

It would also be understood by a skilled artisan how to use thecompositions described herein for therapeutic purposes without undueexperimentation based on the teachings provided throughout thespecification.

The amount of active ingredients or pharmaceutical compounds of theinvention which will be effective in the treatment, inhibition and/orprevention of ED can be determined by standard clinical techniques.Additionally, in vitro assays may be employed to help identify optimaldosage ranges. The precise dose to be utilized will also depend on theroute of administration, and the seriousness of the ED, and should alsobe decided according to the sound medical judgment of the clinician andeach patient's individual circumstances. The specific therapeuticallyeffective dosage level for any particular patient will depend upon avariety of factors including: the type and degree of the response to beachieved; the specific composition and other agent(s), if any, employed;the age, weight, general health, sex and diet of the patient; the timeof administration, route of administration, and rate of excretion of thecomposition; the duration of the treatment; other drugs used incombination or coincidental with the composition; and any other factorswell known in the medical arts. Effective dosages may also beextrapolated from dose-response curves derived from in vitro or animalmodel testing systems.

All patents, patent applications, provisional applications, andpublications referred to or cited herein are incorporated by referencein their entirety, including all figures and tables, to the extent theyare not inconsistent with the explicit teachings of this specification.By citation of various references in this document, Applicants do notadmit any particular reference is “prior art” to their invention.

I claim:
 1. A composition for the treatment or prevention of erectiledysfunction, comprising a therapeutically effective amount of ananti-erectile dysfunction drug (AED), or pharmaceutically acceptablesalt thereof; and cannabis, or extract thereof.
 2. The composition ofclaim 1, wherein the AED comprises at least one of vardenafil, avanafil,sildenafil, tadalafil, and alprostadil.
 3. The composition of claim 1,wherein the AED comprises at least one of vardenafil, avanafil,sildenafil, tadalafil, alprostadil, damiana, horny goat weed, andyohimbine.
 4. The composition of claim 1, wherein the AED comprises atleast one of damiana, horny goat weed, and yohimbine.
 5. The compositionof claim 1, wherein the cannabis extract comprises at least onecannabinoid.
 6. The composition of claim 1, wherein the cannabis extractcomprises cannabidiol (CBD).
 7. The composition of claim 1, wherein thecannabis extract comprises tetrahydrocannabinol (THC).
 8. Thecomposition of claim 1, wherein the cannabis extract comprisescannabidiolic acid (CBDA).
 9. The composition of claim 1, wherein thecannabis extract comprises cannabidivarin (CBDV).
 10. The composition ofclaim 1, wherein the cannabis extract comprises cannabidivarinic acid(CBDVA).
 11. A pharmaceutical composition for treatment or prevention oferectile dysfunction, comprising a therapeutically effective amount ofan anti-erectile dysfunction drug (AED), or pharmaceutically acceptablesalt thereof a cannabinoid, or synthetic variant thereof and apharmaceutically acceptable carrier.
 12. The composition of claim 11,wherein the cannabinoid is selected from cannabidivarin,tetrahydrocannabinol, cannabidiolic acid, cannabidivarinic acid,cannabidiol and combinations thereof.
 13. The composition of claim 11,wherein the synthetic cannabinoid is selected from syntheticcannabidivarin, synthetic tetrahydrocannabinol, synthetic cannabidiolicacid, synthetic cannabidivarinic acid, synthetic cannabidiol, andcombinations thereof.
 14. A method for treatment or prevention oferectile dysfunction (ED) in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of an anti-erectile dysfunction drug (AED), or pharmaceuticallyacceptable salt thereof and a cannabis extract or cannabinoid.
 15. Themethod of claim 14, wherein the cannabinoid is a synthetic cannabinoid.16. The method of claim 14, wherein the cannabis extract or cannabinoidcomprises cannabidiol (CBD).
 17. The method of claim 14, wherein thecannabis extract or cannabinoid comprises tetrahydrocannabinol (THC).18. The method of claim 14, wherein the cannabis extract or cannabinoidcomprises cannabidiolic acid (CBDA).
 19. The method of claim 14, whereinthe cannabis extract or cannabinoid comprises cannabidivarin (CBDV). 20.The method of claim 14, wherein the cannabis extract or cannabinoidcomprises cannabidivarinic acid (CBDVA).